tbuckley/cabot-search huggingface dataset:
A phase I study of isunakinra, an IL-1 alfa/beta inhibitor, in combination with nivolumab for patients with solid tumors refractory to standard therapies.
Authors: Carlos Roberto Becerra, Andrew Scott Paulson, Jan Kowalski, Hans Olivecrona, Maarten de Chateau
Journal: Journal of Clinical Oncology (2023)

e14580 Background: Interleukin-1 is a master cytokine produced by macrophages (IL-1 β) and released upon cell death (IL-1 α). IL-1 upregulates other cytokines in the tumor microenvironment (i.e. IL-6 and IL-8), drives chronic non-resolving inflammation in the tumor, induces cancer cell invasion and metastasis (EMT), has profound effects on immune cells and cancer associated fibroblasts and can attract granulocytic myeloid suppressor cells to the tumor (PMN-MDSC), that in turn inhibit cytotoxic T cell responses. Isunakinra is a small recombinant protein resembling IL-1Ra, with an inhibitory potency 10-20 times higher, that binds to the IL1-R1 and blocks activation of the receptor by both IL-1α and IL-1β. We conducted a phase I dose escalation study with isunakinra as monotherapy and in combination with a PD-1 inhibitor in patients with locally advanced or metastatic solid tumors that had exhausted all treatment options. Methods: Enrolled patients with refractory metastatic solid tumor, ECOG 0-2, on a 3 + 3 dose-escalation trial at three dose levels of isunakinra (15, 25 or 50 mg). Isunakinra was self-administered once daily SC for three weeks followed by 4 additional weeks in combination with nivolumab Q4W at 480 mg, flat dose to complete the DLT period of 7 weeks. Thereafter, isunakinra/nivolumab was continued until week 28. Primary endpoints: DLTs, safety, and pharmacokinetics. Secondary endpoints: tumor and immune monitoring. Results: Enrolled fifteen patients with metastatic or unresectable locally advanced solid tumors (colorectal, pancreatic, triple-negative BC, anal, prostatic, CCA, and appendix) that had received 2-5 prior lines of therapy. Seven SAE occurred in three rapidly deteriorating subjects, all disease related hospitalizations, leading to study withdrawal during the DLT period. No DLTs, irAE or predefined laboratory deviations occurred in any subject. The highest dose, 50 mg, was selected as RP2D. Twelve subjects completed visit week 8, six of them week 12, and four completed the trial. One patient with metastatic colon cancer (MSS, KRAS mut, high TMB) was granted extended treatment for PR and continued response at end of study. Isunakinra exposure totaled 1575 daily doses, 81% during combination with nivolumab, t 1/2 5 hours with no accumulation over time. At 50mg of isunakinra, plasma levels where well above 100 ng/mL, a target for complete IL-1 inhibition. Conclusions: Isunakinra is safe and well-tolerated in combination with standard dose nivolumab. Ongoing expansion cohorts and future studies will explore the safety and efficacy of isunakinra in specific tumors and with other immunotherapy combinations. Clinical trial information: NCT04121442 .
Genomic landscape of <i>CDK6</i> amplification and its potential prognostic value in adult-type diffuse gliomas.
Authors: Xi Yuan, Tianshi Que, Guozhong Yi, Zhiyong Li, Haojie Zheng, Yawei Liu, Xiaoxuan Wang, Xing Zhang, Guanglong Huang
Journal: Journal of Clinical Oncology (2023)

e14038 Background: Glioma is commonly described as a disease of neuroglial cell proliferation. And the gene related to cell cycle pathway alter frequently in glioma including CDKN2A/B, CDK4 and CDK6. CDKN2A/B homozygous deletion is proved to be associated with worse survival in IDH-mut gliomas and meningiomas. However, the correlation between CDK4/6 amplification and the prognosis of glioma remains unclear. Herein, we explored the distribution of CDK4/6 alterations and whether they are the prognostic biomarker of glioma. Methods: A total of 90 patients with adult-type diffuse glioma were enrolled to this retrospective study from our center. Whole genome sequencing (WES) was performed to identify the mutations of the cohort. Results: CDK4 and CDK6 amplified in 17 (18.9%) and 12 (13.3%) patients, respectively. Four patients harbored both CDK4 and CDK6 amplification. The Cox multivariate regression revealed only CDK6 amplification was the independent factor (HR 4.0, 95% CI 1.1-15.2, p=0.041) of overall survival (OS). Interestingly, CDK6 amplification occurred easier in female and trended to be co-mutant with CDKN2A/B homozygous deletion. CDK6 amplification was found to be significantly associated with shorter OS ( p&lt;0.05) of glioblastoma (GBM). Although TERTp was not related to the OS of GBM according to TCGA, patients harboring both TERTp and CDK6 amplification had the significant worst OS ( p&lt;0.001). Conclusions: Our study compared the mutational characteristics of gliomas with CDK4/6 alterations and demonstrated the potential prognostic value of CDK6 amplification, and provide the new basis of precise diagnosis and treatment in gliomas.
Incorporating long non-coding RNA (lncRNA) into genome-wide biomarker screening for prognostic gene signatures of immunotherapy outcomes.
Authors: Xuefeng Wang, Tingyi Li, Vineeth Sukrithan, Aakrosh Ratan, Martin McCarter, John D. Carpten, Howard Colman, Alexandra Ikeguchi, Igor Puzanov, Susanne M. Arnold, Michelle L. Churchman, Patrick Hwu, William S. Dalton, George J. Weiner, Ahmad A. Tarhini
Journal: Journal of Clinical Oncology (2023)

2617 Background: Emerging data have shown that long non-coding RNA (lncRNAs) have the potential to become biomarkers in cancers with potential roles in regulating cell proliferation, apoptosis, migration, invasion and maintenance of stemness during cancer development. In this research, we aimed for a genome-wide biomarker screening approach incorporating lncRNA in order to identify key molecules and pathways involved in ICI response and resistance. Methods: We utilized clinical and transcriptomic data collected under the Total Cancer Care Protocol (NCT03977402) and Avatar project within the Oncology Research Information Exchange Network (ORIEN). We analyzed RNA-seq data from a total of 875 ICI treated pts. A novel resampling-based technique with elastic net regression was utilized for genome-wide biomarker screening, in which Cox regression was used for survival outcomes and logistic regression for a 2-year-based dichotomized outcome. All search was done through 200 resampling steps, each consisting of randomly selecting 80% of pts and 80% of all gene signatures. Moreover, we searched the genes that are most complementary to the established immune cell scores (i.e., Ecotyper and xCell) by incorporating these scores into the regression adjustment. Finally, we applied the same approach to identify prognostic long non-coding RNA (lncRNA) signatures. All analyses were carried out on all ICI pts, as well as on subgroups stratified by cancer type. Results: Of 875 pts treated with ICI, 125 had melanoma, 143 had kidney cancer, 126 had non-small lung cancer, and 110 had head and neck cancer. The genome-wide selection method successfully identified a panel of top prognostic genes and pathways for all cancer types included. In melanoma, the top five prognostic genes were ZDHHC2, CBX4, MET, NTN4, and HLA-DQA1, with 80%, 78%, 77.5%, 77.5%, 76.5% resampling-based selection probability respectively; the top five lncRNAs were AC073655.3, AC116348.3, PITPNA-AS1, AC011447.3, and AL021978.1. When adjusting for the immune scores in the selection model, the top five prognostic protein-coding genes in melanoma were TENM3, POLR2J3, SCCPDH, MET and SIAH1, and the top five lncRNAs were AC007620.2, PITPNA-AS1, HCG11, SLC25A5-AS1, and LINC02258, respectively. Conclusions: Our analysis has successfully identified gene panels of mRNA and lncRNA molecules with potential roles related to ICI mechanisms of action. Ongoing analyses are further investigating the potential mechanisms and pathways linking these molecules and will be presented at the meeting. [Table: see text]
Prevalence of and racial/ethnic distribution of full-body skin examination among sexual and gender minority patients.
Authors: Jincong Q. Freeman, Michelle Verghese, Brian W. Connor, Aniruddha Hazra, Iris Romero, Andrew R. Fisher, Adena E. Rosenblatt
Journal: Journal of Clinical Oncology (2023)

10557 Background: Skin cancer disproportionately affects sexual and gender minorities in the United States. A full-body skin examination (FBSE) can help detect early signs of skin cancer and is an important prevention method. However, there are no national guidelines of routine FBSE for skin cancer. Further, data on FBSE participation among lesbian, gay, bisexual, transgender, and/or queer (LGBTQ+) patients are lacking, and little is known about the racial/ethnic distribution of FBSE in this patient population. Methods: Cross-sectional survey data on FBSE participation and key characteristics were collected from patients who were recruited at clinics and community centers or via social media from August 2022 to January 2023. Eligibility criteria included being at least 18 years old and self-identifying as LGBTQ+. Receipt of an FBSE, assessed by asking patients whether they had ever received an FBSE in the past, was dichotomized as yes and no. Descriptive statistics, i.e., mean (SD) and count (%), were calculated, with distribution comparisons using Student’s t, Pearson’s Chi-square, or Fisher’s exact tests as appropriate. Results: A total of 124 LGBTQ+ patients responded to the survey. The mean age was 32.4 (SD = 12.1) years. Overall, 41.5% of the patients reported ever having received an FBSE in the past. By race/ethnicity, 62.5% of Non-Hispanic Black patients reported ever having received an FBSE, followed by 52.1% of Non-Hispanic White, 28.6% of Hispanic or Latino, 28.6% of multiple races, and 10.5% of Asian ( p= 0.005). By gender identity, 61.5% of transgender male patients reported receipt of an FBSE in the past, followed by 57.1% of transgender female, 39.3% of cisgender female, 35.4% of cisgender male, and 35.0% of genderqueer, non-binary, or gender non-conforming. Comparing patients who reported ever having received an FBSE, those who did not were more likely to not be employed (47.9% vs. 26.0%, p= 0.046), to be on Medicaid (18.5% vs. 6.1%, p= 0.074), to not have visited a dermatologist in the past (41.7% vs. 7.8%, p&lt; 0.001), and to not have been told at an increased risk for skin cancer (87.3% vs. 43.2%, p&lt; 0.001). No significant differences in educational attainment or sexual orientation were observed between patients who reported ever having received an FBSE and those who did not. Conclusions: The prevalence of FBSE was higher among Non-Hispanic Black or Non-Hispanic White LGBTQ+ patients than among those who are Hispanic or Latino, multiracial, or Asian. In addition, our findings suggest that low socioeconomic status and health care utilization may influence FBSE access or participation in LGBTQ+ patients. Strategies for improving equitable access to FBSE among LGBTQ+ patients, particularly among those with ethnic minority background or low socioeconomic status and health care utilization, may be needed.
An exploratory clinical trial on intra-lumbar injection of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.
Authors: Xiaoyun Shang
Journal: Journal of Clinical Oncology (2023)

2043 Background: No standard-of-care treatment was established for recurrent high-grade gliomas (rHGGs) yet. Intrathecal infusion of autologous chimeric antigen receptor-T (CAR-T) cells has displayed potent anti-tumor activity in one patient (Brown et al. N Engl J Med 2016). We evaluated the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of B7H3-specific allogeneic universal CAR-T (B7H3 UCAR-T) cells in patients with rHGGs. Methods: Eligible patients who had received standard treatment for newly-diagnosed high-grade gliomas but failed were treated with 2.5×10 7 B7H3 UCAR-T cells via intra-lumbar injection every month. Eligibility criteria included histologic and/or cytologic rHGGs, B7H3-positive antigen expression rate of &gt;50% in tumor tissue and Karnofsky performance status (KPS) ≥ 40. The primary endpoint was treatment-related adverse events (TAEs); secondary endpoints include overall survival (OS) and objective response rate (ORR); exploratory endpoints were PK and PD characteristics of B7H3 UCAR-T cells. Results: In the 7 patients enrolled, 4 (57.1%) were female, 5 (71.4%) glioblastoma (WHO Grade IV) and 2 (28.6%) diffuse midline glioma (WHO Grade IV), and the mean age was 40.4 years. The most common reported TAEs were increased cerebrospinal fluid (CSF) IL-6 (7/7, 100%), headache (7/7, 100%), increased blood IL-6 (6/7, 86%) and fever (6/7, 86%). No adverse events of grade 3 or greater related to B7H3 UCAR-T cells were reported. All the adverse events recovered or relieved after treatment. No typical or severe systemic cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or graft versus host disease (GvHD) were observed during the study period. Based on Immunotherapy Response Assessment in Neuro-Oncology (iRANO), 3 of 7 patients had response to therapy (42.9%; 95% CI: 15.8 to 75.0) and 7 of 7 patients were stable disease (100%; 95% CI: 64.6 to 100). As of cutoff date (January 30, 2023), two patients died. The median OS was not reached (95% CI: 12.9 to could not be estimated). The median follow-up for OS was 15.6 months (95% CI: 14.7 to 16.1). OS rate at 12 months was 85.7% (95% CI: 48.7 to 97.4). The CAR DNA copy numbers increased 1 day after each administration and persist at least 1 month in cerebrospinal fluid. IL-6 concentrations in CSF and peripheral blood increased after each administration while the change and concentration values in peripheral blood were much lower than those in CSF. Conclusions: In patients with rHGGs, B7H3 UCAR-T cells was not associated with any toxic effects of grade 3 or higher. B7H3 UCAR-T cells resulted in a significantly longer overall survival and a higher objective response rate than history data. B7H3 UCAR-T cells persist well in patients. Clinical trial information: ChiCTR2100047968 .
<i>Caveat emptor</i>: A descriptive analysis of guideline-recommended biomarker inclusion in targeted NGS panels for metastatic non-small cell lung cancer (mNSCLC).
Authors: John Leonard Fox
Journal: Journal of Clinical Oncology (2023)

3124 Background: Next generation sequencing (NGS)-based panels are routinely used in the diagnosis of mNSCLC, guidelines recommending assessing 12 genes for small variants (SV), (EGFR, BRAF, KRAS, MET, ERBB2); fusions (F), (ALK, ROS1, RET, NTRK1, NTRK2, NTRK3); and copy number variants (CNV), (MET) to assess eligibility for targeted drug therapies. Reimbursement is often limited to targeted panels; yet, a comprehensive review of targeted panels’ ability to capture all recommended biomarkers has not been reported. Methods: Targeted panels were classified as ≤50 and 51-100 genes. We searched the DEX Diagnostics Exchange Registry for NGS-based lung cancer and solid tumor targeted panels. Each panel was compared against the 12 recommended genetic variants. If the type of genetic analysis (SV/F/CNV) was unclear, labs were contacted for clarification. Fusion assays by PCR or FISH with reflex testing to NGS were included. Results: 30 targeted NGS panels from 21 commercial labs were identified; 13 (43%) were specific to lung cancer. Six of 13 panels assessing fusions used FISH or PCR not NGS alone. 12 panels reported only SV, 8 small SV/F, 5 SV/CNS, and 5 all three variant types. Only 1 of the 30 panels (51-100 genes) captured all 12 biomarkers with correct variant types. Of 20 panels reporting ALK, RET, and ROS1, only 11(55%) reported fusions. Of the 5 reporting all three variant types, NTRK fusions were most commonly absent. On average, solid tumor panels sequenced twice as many genes (51 vs. 24) but were no more likely to capture all recommended biomarkers ((1/17 (6%) vs. 0/13 (0%), (p&gt;0.05)). The average biomarkers captured in lung vs. solid tumor panels were 7.9 and 6.6, respectively (p&gt;0.05), while in ≤50 gene panels vs. 51-100 gene panels, 7.0 and 7.6, respectively (p&gt;0.05). Conclusions: Of 30 commercially available NGS panels with &lt;100 genes, only one captured all recommended gene variant types for mNSCLC. Failure to capture all biomarkers was independent of panel size or specificity to lung cancer. NGS panels including small variants, fusions, and copy number variants assessed more biomarkers. Medical oncologists and clinical pathologists ordering targeted NGS panels for the management of patients with mNSCLC must ensure they assess all biomarkers relevant to targeted therapies. Insurers reimbursing targeted panels should acknowledge the inadequacy of &lt;100 gene panels alone to provide guideline-concordant molecular diagnostic testing. [Table: see text]
<i>NRG1</i> fusions in solid tumors.
Authors: Brinda Gupta, Sharon Wu, Sai-Hong Ignatius Ou, Sourat Darabi, Kathryn Finch Mileham, Nishant Gandhi, Benjamin Adam Weinberg, Misako Nagasaka, Hossein Borghaei, Patrick C. Ma, Alex Patrick Farrell, George W. Sledge, Ari M. Vanderwalde, Wafik S. El-Deiry, Stephen V. Liu
Journal: Journal of Clinical Oncology (2023)

3132 Background: NRG1 fusions are rare but actionable genomic drivers that occur across a growing number of tumor types. NRG1 has an EGF-like domain that serves as a ligand for ErbB (HER3) receptors, thereby inducing heterodimerization, usually with HER2, and subsequent activation of relevant downstream signaling pathways. Agents targeting the HER2/HER3 pathway have shown early clinical promise in NRG1 fusion-positive cancers: currently zenocutuzumab has FDA Fast Track Designation for tumors harboring NRG1-fusions. Here, we update the incidence and characterization of NRG1 fusions across tumor types. Methods: Samples were submitted for clinical molecular profiling at Caris Life Sciences via Caris MI Tumor Seek (Phoenix, AZ). Gene fusion detection was performed on mRNA isolated from a formalin-fixed paraffin-embedded tumor sample using the Illumina NovaSeq platform (Illumina, Inc., San Diego, CA) and Agilent SureSelect Human All Exon V7 bait panel (Agilent Technologies, Santa Clara, CA). All NRG1 fusions with ≥ 3 junction reads were identified for manual review and for characterization of fusion class, intact functional domains, domain prediction, breakpoints, frame retention and co-occurring alterations by next-generation sequencing. Results: In an analysis of 169,273 tumor specimens, 261 unique tumors with an NRG1 fusion were identified for an overall incidence of 0.154% across tumors. NRG1 fusions were most frequently detected in NSCLC, breast cancer, ovarian cancer, pancreatic ductal adenocarcinoma, colorectal cancer, cholangiocarcinoma, prostate cancer, bladder and urothelial cancers, esophagogastric cancers and less commonly, prostate cancer, soft tissue sarcoma, anal cancer, salivary gland cancers, head and neck cancer, small intestine cancer, small cell lung cancer, endometrial cancer, thyroid cancer, neuroendocrine cancer, high grade glioma, and melanoma. The highest incidence was in breast cancer (0.301%), followed by cholangiocarcinoma (0.263%), NSCLC (0.232%), carcinoma of unknown primary (0.215%), pancreatic ductal adenocarcinoma (0.190%), ovarian cancer (0.174%), bladder cancer (0.148%), esophageal cancer (0.145%) and vulvar cancers (0.145%). There were 153 unique NRG1 fusion partners. The most common fusion partner was CD74 (12.37%), followed by SLC3A2 (8.13%), ATP1B1 (4.59%), and RBPMS (4.24%). Conclusions: NRG1 fusions are rare but actionable genomic events with significant heterogeneity of tumor type and fusion partner.
Prevalence and clinical correlations of Lynch syndrome (LS) in northeast Brazil.
Authors: Rosane Oliveira Sant'Ana, Isabelle Joyce de Lima Silva-Fernandes, Pedro Lucena Aquino, Larissa Mont'Alverne De Arruda, Flávio da Silveira Bitencourt, Maria Claudia dos Santos Luciano, Maria Júlia Barbosa Bezerra, Paulo Goberlânio de Barros Silva, Clarissa Gondim Picanço-Albuquerque, Francisca Fernanda Barbosa Oliveira
Journal: Journal of Clinical Oncology (2023)

e22547 Background: LS is an autosomal dominant inherited condition with high risk for colorectal (CRC) and endometrial cancer, mostly. The LS is determined by a deficient Mismacht Repair (dMMR) system following germline mutations of MSH2, MLH1, MSH6, PMS2 and EPCAM genes. Identification of LS patients promotes adequate prevention and possible reduction of mortality for these population. The present study objetives to determine the frequencies of LS in a mixed race population from Northeast of Brazil, usually not represented in literature and characterize its genotype-fenotype feature. Methods: Our study prospectively screened 150 cancer patients (mostly CRC) with risk for LS according to NCCN guideline v2020 and performed germline mutational testing with a 33-multigene panel by NGS. Results: Median age was 48years and mainly female gender (63,3%). CRC was the most frequent tumor (n = 121, 80.7%), followed by breast cancer (11.3%), endometrium cancer (9.3%) and others (3,3% each). CCR patients presented MMR deficiency (dMMR) detected by IHC in a frequency of 29.3%. It was identified 32.7% of PV or PPV (according to ACMG criteria) with 20.7% for LS genes (mMMR). Two patients had 2 genes mutated. For CRC patients there was association of stage I-II tumors (p = 0,009) and right location (p &lt; 0,001) with mutational status. There is no significant correlation of mutational status and other clinical caractheristics. MSH2 was the most frequently mutated (11) followed by MSH6 (10), heterozygous MUTYH (5), homozygous MUTHY (3), PMS2 (7), APC (4) and MLH1 (3) and others. MSH2 most frequent variants were c.388 389del (4) and c.2581C &gt; T (2). Of the NCCN criteria for LS, personal history of CRC or endometrial cancer under 50 years of age was the most prevalent (67.3%) followed by tumoral dMMR (37.3%). dMMR tumor was the criteria with the best accuracy (sensibility 80.0 – 100.0% and specificity 76.6 – 93.5%) for LS detection. Patients with more than three criteria presented high sensibility and specificity values (80.6 and 90.3%, respectively). There were more than 60% of variants of uncertain significance variants (VUS). Conclusions: Our study detected a lower frequency of PV of LS genes (20,7%) than others even from Brazil, however it differs from these on criteria for LS (more inclusive), sequencing method (NGS multigene painel) and the population (derived from mixed caucasians, africans and native Indians). LS genotype correlates with CRC stages I-II and from right colon location. The most frequent mutated gene was MSH2 (c.388 389del and c.2581C &gt; T). MLH1 was the less frequent mutated gene in our cohort.